Controlled Release Dosage Form Containing Lercanidipine and a Performance-enhancing Acid

ABSTRACT

A controlled release dosage form containing lercanidipine, or a salt thereof, a performance-enhancing acid, and at least one other pharmaceutical excipient exhibits enhanced in vitro dissolution of lercanidipine, enhanced storage stability based upon the reduced degradation of lercanidipine, and/or enhanced in vivo bioavailability of lercanidipine as compared to an otherwise similar controlled release dosage form excluding the performance-enhancing acid but containing the same amount of lercanidipine.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of and claims the priority ofU.S. Provisional Application No. 60/827,360 filed Sep. 28, 2006, theentire disclosure of which is hereby incorporated by reference.

FIELD OF THE INVENTION

This invention pertains to a controlled release dosage form for thecontrolled delivery of lercanidipine. More particularly, it pertains toan osmotic device that comprises lercanidipine, at least one swellablepolymer, and a carboxylic acid. The invention also provides a method oftreating a disorder or disease that is therapeutically responsive tolercanidipine.

BACKGROUND OF THE INVENTION

Lercanidipine (methyl1,1,N-trimethyl-N-(3,3-diphenylpropyl)-2-aminoethyl1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)pyridine-3,5-dicarboxylate) isa highly lipophilic dihydropyridine calcium antagonist (calcium channelblocker) with a long duration of action and high vascular selectivity.It has a high affinity for and competitively antagonizes thedihydropyridine subunit of the L-type calcium channel. Lercanidipine isprimarily a vasodilator that lowers blood pressure by decreasingperipheral vascular resistance at the level of the small arterioles.

Lercanidipine is subject to photochemical degradation when exposed toUV-A radiation, and it is also subject to degradation and oxidation insolution.

U.S. Pat. No. 4,705,797 to Nardi et al., U.S. Pat. No. 5,767,136 toSartani et al., U.S. Pat. No. 4,968,832 to Bianchi et al., U.S. Pat. No.5,912,351 to Leonardi et al., and U.S. Pat. No. 5,696,139 to Leonardi etal., describe lercanidipine along with methods for its preparation andits resolution into the individual enantiomers.

The hydrochloride salt of lercanidipine has been approved for thetreatment of hypertension and has been marketed since 1996 in severalEuropean countries under the trademark Zanidip™ (Recordati S.p.A.(Milan, Italy)). The recommended starting oral dose of lercanidipine HClis 10 mg once daily and is increased after at least 2 weeks, ifnecessary, to 20 mg daily. Upon oral administration of an immediaterelease form of lercanidipine, peak plasma level (Tmax) occurs 1-3 hoursfollowing administration.

U.S. Pat. No. 6,852,737 to Bonifacio et al. discloses that lercanidipinehydrochloride shows polymorphic features and crystallizes into differentcrystalline forms depending on the process followed and on the solventsused. Crude lercanidipine hydrochloride Form (A), which has a meltingpoint of about 150-152° C. (DSC peak) and comprises about 3-4% (w/w)ethyl acetate, crude lercanidipine hydrochloride Form (B) which has amelting point of about 131-135° C. (DSC peak) and comprises about0.3-0.7% (w/w) ethyl acetate, lercanidipine hydrochloride crystallineForm (I), and lercanidipine hydrochloride crystalline Form (II) areprovided.

U.S. Pregrant Pub. No. 2003/0069285 to Leonardi et al. disclosessolvates of lercanidipine hydrochloride with organic solvents andlercanidipine hydrochloride crystalline forms obtained from saidsolvates, such as lercanidipine hydrochloride crystalline Form (III) and(IV).

U.S. Pregrant Pubs. No. 2003/0083355, No. 2004/0204459, and No.2005/0239847 all to Bonifacio et al. disclose novel lercanidipine crudeForms (A), and (B) and novel lercanidipine hydrochloride crystallineForms (I) and (II) obtained from said crude Forms.

U.S. Pregrant Pub. No. 2006/0047125 to Leonardi et al. discloses newaddition salts of lercanidipine comprising lercanidipine and an acidcounterion. The acid counterion is selected from the group consistingof: (i) inorganic acids, (ii) sulfonic acids, (iii) monocarboxylicacids, (iv) dicarboxylic acids, (v) tricarboxylic acids, and (vi)aromatic sulfonimides, with the proviso that said acid counterion is nothydrochloric acid.

U.S. Pregrant Pub. No. 2006/0073200 to Leonardi et al. discloses amodified release lercanidipine pharmaceutical composition comprising atleast one waxy substance and a therapeutically effective amount oflercanidipine. The oral administration of the modified releaselercanidipine pharmaceutical composition contained in capsules to apatient results in a mean lercanidipine plasma concentration of greaterthan 0.5 ng/ml for the full time period of about 24 hours afteradministration of the composition to the patient.

U.S. Pregrant Pub. No. 2006/0165788 to Abramowitz et al. discloses amodified release composition that release pulses of lercanidipine basedon the pH of the use environment.

U.S. Pregrant Pub. No. 2006/0165789 to Abramowitz et al. discloses amodified release bead composition which provides modified release oflercanidipine independent of pH and therefore provides release oflercanidipine even upon exposure to the low pH use environments, such asgastric fluid.

PCT International Application Publication No. WO 05/053689 discloses apharmaceutical composition comprising lercanidipine or an analog or apharmaceutically acceptable salt thereof as an active substance and apharmaceutically acceptable vehicle. The composition upon oraladministration to a mammal in need thereof releases the active substancein a controlled manner.

Lercanidipine and its salts are virtually insoluble in water, with anaqueous solubility of about 5 g/ml. Lercanidipine is essentiallyinsoluble in gastrointestinal pH range of 1 to 8. Lercanidipine isclassified as a low permeable drug, as defined by the FDA, and displaysextensive presystemic first pass elimination, as a result of its being asubstrate for cytochrome P450 IIIA4 isoenzyme. Lercanidipineadministered in the absence of food is not entirely absorbed whichresults in low and variable bioavailability. The dependence of effectivedosing and absorption of lercanidipine upon co-administration of food isundesirable due to fluctuations in effectiveness, inter-patientvariability, and poor patient acceptance and compliance.

Given the importance of lercanidipine in the treatment of variousdisorders, there remains a need in the art for improved lercanidipineoral dosage forms.

SUMMARY OF THE INVENTION

The controlled release solid dosage form of the invention seeks toovercome one or more disadvantages present in other dosage formscontaining lercanidipine. The controlled release solid dosage form ofthe present invention overcomes the difficulties caused by the lowsolubility of lercanidipine in aqueous media thereby providing goodlercanidipine absorption and bioavailability over a period of at least24 hours compared to currently available lercanidipine compositions.

In one aspect, the dosage form is an osmotic device comprising: 1) acore comprising lercanidipine, or a pharmaceutically acceptable saltthereof, in admixture with a performance-enhancing acid and one or moreother pharmaceutical excipients; and 2) a wall enveloping the core andcomprising at least one preformed passageway. The dosage form provides acontrolled release of lercanidipine over a period of about 8-36 hours,about 10-30 hours, or about 12-24 hours, or about 18-24 hours.

Some embodiments of the invention comprise a salt of lercanidipine. Thesalt can be selected from mineral acid or organic acid salts oflercanidipine. In some embodiments, the performance-enhancing acid is anorganic acid and the acid used to form the salt of the lercanidipine isa mineral acid. In some embodiments, the organic acid is a non-aromaticcarboxylic acid; a monocarboxylic acid, such as acetic acid,(+)-L-lactic acid, DL-lactic acid, DL-mandelic acid, gluconic acid,cinnamic acid, salicylic acid, and gentisic acid; a dicarboxylic acid,such as oxalic acid, 2-oxo-glutaric acid, malonic acid, (−)-L-malicacid, mucic acid, (+)-L-tartaric acid, fumaric acid, succinic acid,maleic acid, and terephthalic acid; a hydroxy-carboxylic acid; ahydroxy-dicarboxylic acid; a tricarboxylic acid, such as citric acid, oraromatic carboxylic acid; sulfonic acids, such as methanesulfonic acid,benzenesulfonic acid, toluenesulfonic acid, andnapthalene-1,5-disulfonic acid; alpha-hydroxy acids such as tartaricacid, citric acid, ascorbic acid and malic acid; and aromaticsulfonimides such as saccharin. In some embodiments, the mineral acid ishydrochloric acid, hydrobromic acid, sulfuric acid, sulfonic acid,sulfamic acid, phosphoric acid and nitric acid. Specificpharmaceutically acceptable salts of lercanidipine, include but are notlimited to, the hydrochloride, besylate and napadisylate salts. Theperformance-enhancing acid can be, as described herein, a monocarboxylicacid, a dicarboxylic acid, a tricarboxylic acid, a hydroxy-carboxylicacid, a hydroxy-dicarboxylic acid, a hydroxy-tricarboxylic acid, analpha-hydroxycarboxylic acid or a non-aromatic organic acid.

Another aspect of the invention provides an osmotic device, wherein thecore thereof comprises lercanidipine (or a pharmaceutically acceptablesalt thereof), a performance-enhancing acid, an osmotic agent, and atleast one swelling polymer, and optionally one or more other materials,e.g. pharmaceutical excipients, as discussed herein.

The dosage form of the invention can be used to treat a disease ordisorder that is therapeutically responsive to lercanidipine. Bytherapeutically responsive disease or disorder is meant that a subjectsuffering from such a disease or disorder will enjoy a clinical benefitupon administration of one or more osmotic devices of the inventionaccording to a defined dosing regimen. Exemplary therapeuticallyresponsive diseases or disorder include hypertension, fibrinolysis,atherosclerosis, coronary heart disease (e.g., chronic stable angina,myocardial infarction), congestive heart failure, and cerebrovasculardiseases such as cerebral infarction and cerebral apoplexy. The osmoticdevice of the invention can also be used to improve memory in a subjectand reduce the incidence of stroke. The dosage form can contain atherapeutically effective amount of lercanidipine such that a single ortwo or more dosage forms will together result in a unit dose oflercanidipine. Any suitable dosing regimen can be used. The osmoticdevice can be administered once, twice, or three times daily, weekly,biweekly, monthly, bimonthly, quarterly, semiannually, annually, or acombination thereof as required to provide the desired clinical benefitto a subject.

The dosage form can further comprise at least one other pharmaceuticallyactive agent (drug), whereby the dosage form can comprise two or moredifferent drugs. Such a dosage form would be useful for the treatment ofa disease or disorder that is therapeutically responsive tolercanidipine and/or any other drug(s) present in the dosage form.

Other features, advantages and embodiments of the invention will becomeapparent to those skilled in the art by the following description, andaccompanying examples.

BRIEF DESCRIPTION OF THE FIGURES

The following drawings are part of the present specification and areincluded to further demonstrate certain aspects of the invention. Theinvention may be better understood by reference to one or more of thesedrawings in combination with the detailed description of the specificembodiments presented herein.

FIG. 1 depicts a lercanidipine in vitro dissolution profile for theosmotic device described in Example 1.

FIG. 2 depicts the predicted release profiles of the osmotic devicecontaining lercanidipine 30 mg strength in the core and lercanidipine 10mg strength in an immediate or rapid release external drug-containingcoat disclosed in Example 5.

FIG. 3 depicts the predicted release profiles of the osmotic devicecontaining lercanidipine 50 mg strength in the core and lercanidipine 10mg strength in an immediate or rapid release external drug-containingcoat disclosed in Example 5.

FIG. 4 depicts the release profile of the osmotic device containingfumaric acid disclosed in Example 6.

FIG. 5 depicts the release profile of the osmotic device containingoxalic acid disclosed in Example 6.

FIG. 6 depicts the release profile of the osmotic device containingsuccinic acid disclosed in Example 6.

FIG. 7 depicts the release profile of the osmotic device containingtartaric acid disclosed in Example 6.

FIG. 8 depicts the release profile of the osmotic device containingcitric acid disclosed in Example 6.

FIG. 9 depicts the release profile of the osmotic device containinglercanidipine 30 mg strength in the core and lercanidipine 10 mgstrength in an immediate or rapid release external drug-containing coatdisclosed in Example 8.

FIG. 10 depicts the release profile of the osmotic device containinglercanidipine 50 mg strength in the core and lercanidipine 10 mgstrength in an immediate or rapid release external drug-containing coatdisclosed in Example 8.

DETAILED DESCRIPTION OF THE INVENTION

The invention may be better understood by reference to the followingdefinitions provided herein.

By “performance-enhancing acid” is meant an organic acid, in thecontrolled release dosage form, that enhances the bioavailability oflercanidipine when administered to a subject in need thereof and/or thatexhibits reduced degradation (increased stability) of lercanidipineduring storage, as compared to a control osmotic device excluding theperformance-enhancing acid. A performance-enhancing acid may alsoincrease the rate of release of lercanidipine or increase the overallamount of lercanidipine released upon exposure to an aqueous environmentof use or following administration to a subject in need thereof ascompared to an otherwise similar (control) osmotic device excluding theperformance-enhancing acid. As a result, the performance-enhancing acidenhances the in vitro and/or in vivo performance of the controlledrelease dosage form, whereby the dosage form provides an improvedbioavailability of lercanidipine or possesses an improved storagestability (improved shelf-life based upon the reduced degradation oflercanidipine) as compared to an otherwise similar dosage formcontaining the same amount of lercanidipine but excluding theperformance-enhancing acid.

A performance-enhancing acid can comprise a monocarboxylic acid,dicarboxylic acid, tricarboxylic acid, hydroxy-carboxylic acid,hydroxy-dicarboxylic acid, hydroxy-tricarboxylic acid, nonaromaticorganic acid, or a combination thereof. In some embodiments, theperformance-enhancing acid is citric acid, maleic acid, ascorbic acid,fumaric acid, oxalic acid, succinic acid or a combination thereof.

By “immediate release” is meant a release of an active agent to anenvironment over a period of seconds to no more than about 30 minutesonce release has begun and release begins within a second to no morethan about 15 minutes after administration.

By “rapid release” is meant a release of an active agent to anenvironment over a period of 1-59 minutes or 1 minute to three hoursonce release has begun and release can begin within a few minutes afteradministration or after expiration of a delay period (lag time) afteradministration.

By “controlled release” is meant a release of an active agent to anenvironment over a period of about eight hours up to about 12 hours, 16hours, 18 hours, 20 hours, a day, or more than a day. A controlledrelease can begin within a few minutes after administration or afterexpiration of a delay period (lag time) after administration.

By “sustained release” is meant a controlled release of an active agentto maintain a constant drug level in the blood or target tissue of asubject to which the device is administered.

By “extended release” is meant a controlled release of an active agentfrom a dosage form to an environment over an extended period of time. Asused herein, the term “extended release” profile assumes the definitionas widely recognized in the art of pharmaceutical sciences. An extendedrelease dosage form will release drug at substantially constant rateover an extended period of time or a substantially constant amount ofdrug will be released incrementally over an extended period of time. Theterm “extended release”, as regards to drug release, includes the terms“controlled release”, “prolonged release”, “sustained release”, or “slowrelease”, as these terms are used in the pharmaceutical sciences.

A delayed but controlled release dosage form is one that provides adelayed release of a drug followed by a controlled release of the drug.By delayed release is meant any formulation technique wherein release ofthe active substance from the dosage form is modified to occur at alater time than that from a conventional immediate release product. Inother words, the beginning of the controlled release of drug is delayedby an initial period of time. The period of delay is generally about 5minutes to 10 hours, or 30 minutes to 10 hours, or 1 hour to 10 hours.

A zero-order release profile characterizes the release profile of adosage form that releases a constant amount of drug per unit time. Apseudo-zero order release profile is one that approximates a zero-orderrelease profile. A dissolution curve shows a zero or pseudo-zero orderrelease profile if its release rate remains constant (or relativelyconstant within ±10% of the average value) in the interval of time0≦a<t≦b. Any profile following the equation:

(M(t)/M _(r))=k(t−a)^(n) 0.9≦n≦1.1

has the following release rate equation:

(1/M)(dM/dt)=kn(t−a)^(n-1)

A sigmoidal release profile characterizes the release profile of adosage form that releases a drug in a controlled manner but very slowlyduring a first release period, then more rapidly during a second releaseperiod and finally very slowly during a third release period such thatthe release profile resembles a sigmoid. A dissolution curve shows asigmoid release profile within a certain interval of time 0≦a<t≦b if itsrelease rate reaches a single maximum within the interval (a, b)excluding the extremes. That is equivalent to consider a point of timeT* so that the release rate is an increasing function of time for a≦t<T*and a decreasing function of time, as determined by the followingequation:

Weibull Function

(M(t)/M _(T))=W _(inf{)1−exp{−[(t−t _(i))/β]^(α)}} Parameter ranges:

t₁: between 0 and 3β: between 7 and 12α: 1<α<3W_(inf): between 0.5 and 1.1

A first order release profile characterizes the release profile of adosage form that releases a percentage of a drug charge per unit time. Apseudo-first order release profile is one that approximates a firstorder release profile. A dissolution curve shows a first or pseudo-firstorder release profile within a certain interval of time 0≦a<t≦b if itsrelease rate is a continue monotone decreasing function of time.Specifically, a dissolution curve shows a first order profile wheneverits release rate is proportional to the remaining undissolved amount ofdrug, as determined by the following equation:

(M(t)/M _(T))=1−exp(−kt)

A dissolution curve shows a pseudo-first order profile when the drugrelease rate decreases with time as described by the Fickian oranomalous Fickian diffusion controlled release equation:

(M(t)/M _(T))=kt ^(n), 0.3≦n≦0.7

By “unitary core” is meant the core of an osmotic device that is notdivided into two or more layers or laminas. The core is considered to bethe composition enclosed within the wall, e.g. semipermeable membrane,of the osmotic device. The ingredients of the core may be present as aheterogeneous mixture or homogeneous mixture. A homogeneous mixture isone wherein all of the ingredients have been thoroughly mixed such thatthe composition of the formulation is substantially the same throughoutdifferent portions of the core. The combined step of mixing and directlycompressing the ingredients of the core generally provides a homogeneousmixture. A heterogeneous mixture is one wherein the ingredients of thecore are divided into two or more groups that are processed separatelyto form two or more respective blends, at least one of which containsdrug and at least one of which contains the osmotic agent. The blendsare then mixed together and compressed to form the unitary core. Aheterogeneous mixture can be obtained by wet granulation, drygranulation, pelleting or combinations thereof.

The core of the osmotic device of the present invention compriseslercanidipine (or a pharmaceutically acceptable salt thereof), aperformance-enhancing acid (for example, citric acid), an osmotic agent,and at least one swelling polymer, and can further comprise one or moreother materials, e.g. pharmaceutical excipients, as discussed herein.

The osmotic device of the invention can comprise osmotically effectivesolutes or osmotic agents, i.e. osmagents, that are capable of beingtotally or partially solubilized in the fluid. These osmagents can aidin either the suspension or dissolution of lercanidipine from the core.Exemplary osmagents include organic and inorganic compounds such assalts, acids, bases, chelating agents, sodium chloride, lithiumchloride, magnesium chloride, magnesium sulfate, lithium sulfate,potassium chloride, sodium sulfite, calcium bicarbonate, sodium sulfate,calcium sulfate, calcium lactate, d-mannitol, urea, tartaric acid,raffinose, sucrose, alpha-d-lactose monohydrate, glucose, magnesiumsuccinate, sodium succinate, sodium butyrate, sodium fumarate, sodiumbenzenesulfonate, sodium toluenesulfonate, sodium methanesulfonate,combinations thereof and other similar or equivalent materials which arewidely known in the art. U.S. Pat. No. 4,077,407 to Theeuwes et al., theentire disclosure of which is hereby incorporated by reference,discloses suitable osmagents.

One or more osmopolymers can also be included in the core of the deviceto aid in the delivery of lercanidipine. Osmopolymers are well known tothose of ordinary skill in the osmotic device art and well described inthe patent and scientific literature. Exemplary osmopolymers includehydrophilic polymers that swell upon contact with water. Osmopolymersmay be of plant or animal origin, or synthetic. Examples of osmopolymersinclude: poly(hydroxy-alkyl methacrylates) with molecular weight of30,000 to 5,000,000, poly(vinylpyrrolidone) with molecular weight of10,000 to 360,000, anionic and cationic hydrogels, polyelectrolytecomplexes, poly(vinyl alcohol) having low acetate residual, optionallycross-linked with glyoxal, formaldehyde or glutaraldehyde and having adegree of polymerization of 200 to 30,000, a mixture of methylcellulose, cross-linked agar and carboxymethylcellulose, a mixture ofhydroxypropyl methylcellulose and sodium carboxymethylcellulose, sodiumcarboxymethylcellulose, hydroxypropyl methylcellulose, polyethyleneoxide, polymers of N-vinyllactams, polyoxyethylene-polyoxypropylenegels, polyoxybutylene-polyethylene block copolymer gels, carob gum,polyacrylic gels, polyester gels, polyurea gels, polyether gels,polyamide gels, polypeptide gels, polyamino acid gels, polycellulosicgels, carbopol acidic carboxy polymers having molecular weights of250,000 to 4,000,000, Cyanamer polyacrylamides, cross-linkedindene-maleic anhydride polymers, Good-Rite™ polyacrylic acids havingmolecular weights of 80,000 to 200,000, Polyox™ polyethylene oxidepolymers having molecular weights of 100,000 to 5,000,000, starch graftcopolymers, and Aqua-Keeps™ acrylate polymer polysaccharides. Thesematerials swell or expand to an equilibrium state when exposed to wateror other biological fluids. This volume expansion is used to physicallyforce the pharmaceutical agent out through openings that have beenformed in the wall, shell or coating during manufacture. Exemplaryosmopolymers are disclosed in U.S. Pat. No. 5,422,123; U.S. Pat. No.4,783,337; U.S. Pat. No. 4,765,989; U.S. Pat. No. 4,612,008; U.S. Pat.No. 4,327,725; U.S. Pat. No. 4,609,374; U.S. Pat. No. 4,036,228; U.S.Pat. No. 4,992,278; U.S. Pat. No. 4,160,020; U.S. Pat. No. 4,615,698.The osmopolymers generally swell or expand to a very high degree,usually exhibiting a 2 to 60 fold volume increase. The osmopolymers canbe non-cross-linked or cross-linked. The swellable, hydrophilic polymersare, in one embodiment, lightly cross-linked, such as cross-links beingformed by covalent or ionic bonds.

The semipermeable membrane of the osmotic device is formed of a materialthat is substantially permeable to the passage of fluid from theenvironment of use to the core and substantially impermeable to thepassage of active agent from the core. Many common materials that form asemipermeable wall which are known by those of ordinary skill in the artof pharmaceutical sciences are suitable for this purpose. Exemplarymaterials are cellulose esters, cellulose ethers and celluloseesters-ethers. However, it has been found that a semipermeable membranecomprising cellulose acetate (CA) and poly(ethylene glycol) (PEG), inparticular PEG 400, performs well when used in combination with theother materials required in the present osmotic device. This particularcombination of CA and PEG provides a semipermeable membrane that givesthe osmotic device a well controlled release profile for the activeagent in the core and that retains its chemical and physical integrityin the environment of use. The ratio of CA:PEG generally ranges fromabout 50-99% by weight of CA:about 50-1% by weight of PEG, and about 95%by weight of CA:about 5% by weight of PEG. The ratio can be varied toalter permeability and ultimately the release profile of the osmoticdevice. Other suitable materials can include a selected member of thegroup of cellulose acylates such as cellulose acetate, cellulosediacetate, cellulose triacetate and combinations thereof. Many suitablepolymers, include those disclosed in Argentine Patent No. 199,301, U.S.Pat. No. 6,004,582 and references cited herein, the disclosures of whichare hereby incorporated by reference.

Representative materials for making the semipermeable membrane include amember selected from the group consisting of cellulose acylate,cellulose diacylate, cellulose triacylate, cellulose acetate, cellulosediacetate, cellulose triacetate, mono, di and tricellulose alkanylates,mono, di and tricellulose aroylates, and the like. Exemplary polymersinclude cellulose acetate having a substitution degree (D.S.) up to 1and an acetyl content up to 21%; cellulose acetate having an acetylcontent of 32 to 39.8%; cellulose diacetate having a D.S. of 1 to 2 andan acetyl content of 21 to 35%; cellulose triacetate having a D.S. of 2to 3 and an acetyl content of 35 to 44.8%; and the like. More specificcellulosic polymers include cellulose propionate having a D.S. of 1.8and a propionyl content of 39.2 to 45% and a hydroxyl content of 2.8 to5.4%; cellulose acetate butyrate having a D.S. of 1.8, an acetyl contentof 13 to 15% and a butyryl content of 34 to 39%; cellulose acetatebutyrate having an acetyl content of 2 to 29%; a butyryl content of 17to 53% and a hydroxyl content of 0.5 to 4.7%; cellulose triacylateshaving a D.S. of 2.9 to 3 such as cellulose trivalerate, cellulosetrilaurate, cellulose tripalmitate, cellulose trisuccinate, andcellulose trioclanoate; cellulose diacylates having a D.S. of 2.2 to 2.6such as cellulose disuccinate, cellulose dipalmitate, cellulosedioclanoate, cellulose dipentale, and the like. Additional semipermeablepolymers include acetaldehyde dimethyl acetate, cellulose acetate ethylcarbamate, cellulose acetate phthalate for use in environments having alow ph, cellulose acetate methyl carbamate, cellulose acetate dimethylaminoacetate, semipermeable polyamides, semipermeable polyurethanes,semipermeable sulfonated polystyrenes, cross-linked selectivelysemipermeable polymers formed by the coprecipitation of a polyanion anda polycation as disclosed in U.S. Pat. No. 3,173,876, U.S. Pat. No.3,276,586, U.S. Pat. No. 3,541,005, U.S. Pat. No. 3,541,006, and U.S.Pat. No. 3,546,142; semipermeable polymers as disclosed by Loeb andSourirajan in U.S. Pat. No. 3,133,132; lightly cross-linked polystyrenederivatives; cross-linked poly(sodium styrene sulfonate), cross-linkedpoly(vinylbenzyltrimethyl ammonium chloride). These and others polymersare disclosed in U.S. Pat. No. 3,845,770, U.S. Pat. No. 3,916,899, U.S.Pat. No. 4,765,989 and U.S. Pat. No. 4,160,020; and in Handbook ofCommon Polymers (Scott, J. R. and Roff, W. J., eds.; 1971; CRC Press,Cleveland, Ohio).

The cellulose esters differ in their cellulose chain length and the typeand amount of ester groups attached to the chain. For celluloseacetates, as the amount of acetyl content increases, the permeabilitydecreases. The cellulose acetate grade 1 comprises 7-10% by weight ofhydroxyl groups and has a viscosity of 200-280 seconds as determined byASTM Method D 1343. The cellulose acetate grade 2 comprises 3-5% byweight of hydroxyl groups and has a viscosity of 6 to 45 seconds. Thecellulose acetate grade 3 comprises 3-5% by weight of hydroxyl groupsand has a viscosity of 100 to 240 seconds.

Some exemplary grades of cellulose acetate that are suitable for use inthe making the semipermeable membrane are also described in the tablebelow, which is included by way of example. Cellulose acetate ofdiffering grades is readily available from Eastman Chemical Company(Kingsport, Tenn., USA).

Cellulose Hydroxyl Content Acetyl Content Viscosity* Acetate (% by wt.)(% by wt.) (seconds) Grade 1  7-10 30-36 200-280 Grade 2 3-5 37-43  6-45Grade 3 3-5 37-43 100-240 *Viscosity determined as set forth in ASTMD817 (Formula A) and D1343, the disclosure of which is herebyincorporated by reference.

Plasticizers can be included in the present device to modify theproperties and characteristics of the polymers used in the coats or coreof the device. As used herein, the term “plasticizer” includes allcompounds capable of plasticizing or softening a polymer or binder usedin invention. The plasticizer should be able to lower the meltingtemperature or glass transition temperature (softening pointtemperature) of the polymer or binder. Plasticizers, such as lowmolecular weight PEG, generally broaden the average molecular weight ofa polymer in which they are included thereby lowering its glasstransition temperature or softening point. Plasticizers also generallyreduce the viscosity of a polymer. It is possible the plasticizer willimpart some particularly advantageous physical properties to the osmoticdevice of the invention.

Plasticizers useful in the invention can include, by way of example andwithout limitation, low molecular weight polymers, oligomers,copolymers, oils, small organic molecules, low molecular weight polyolshaving aliphatic hydroxyls, ester-type plasticizers, glycol ethers,poly(propylene glycol), multi-block polymers, single block polymers, lowmolecular weight poly(ethylene glycol), citrate ester-type plasticizers,triacetin, propylene glycol and glycerin. Such plasticizers can alsoinclude ethylene glycol, 1,2-butylene glycol, 2,3-butylene glycol,styrene glycol, diethylene glycol, triethylene glycol, tetraethyleneglycol and other poly(ethylene glycol) compounds, monopropylene glycolmonoisopropyl ether, propylene glycol monoethyl ether, ethylene glycolmonoethyl ether, diethylene glycol monoethyl ether, sorbitol lactate,ethyl lactate, butyl lactate, ethyl glycolate, dibutylsebacate,acetyltributylcitrate, triethyl citrate, acetyl triethyl citrate,tributyl citrate and allyl glycolate. All such plasticizers arecommercially available from sources such as Aldrich or Sigma ChemicalCo. It is also contemplated and within the scope of the invention, thata combination of plasticizers may be used in the present formulation.The PEG based plasticizers are available commercially or can be made bya variety of methods, such as disclosed in Poly(ethylene glycol)Chemistry: Biotechnical and Biomedical Applications (J. M. Harris, Ed.;Plenum Press, NY) the disclosure of which is hereby incorporated byreference.

In one embodiment of the invention the membrane ruptures during use ofthe osmotic device to form a spaced away second aperture such that thedevice provides an increased release rate of active agent during use ascompared to a control osmotic device which membrane does not rupture,and the passageways together provide a controlled release of thecontents of the core. The preformed passageway does not connect with thepassageway formed in situ (in the environment of use) by rupture,meaning that the second passageway, after being formed, remains spacedaway from the preformed passageway.

The osmotic device of the invention can comprise a water soluble and/orerodible coating, which is inert or which contains drug. This coatingwould cover and surround the semipermeable membrane and plug anypreformed passageway in the membrane if the passageway had been formedprior to addition of the coating. The water soluble and/or erodiblecoating will generally comprise an inert and non-toxic material that isat least partially, and optionally substantially completely, soluble orerodible in an environment of use. Selection of materials suitable forthe inert or drug-containing water soluble coatings will depend upon thedesired release rate of drug from the drug-containing coating and uponthe desired separation of drug delivery from the core versus thedrug-containing coating. A rapidly dissolving coat will be soluble inthe buccal cavity and/or upper gastrointestinal (GI) tract, such as thestomach, duodenum, jejunum or upper small intestines. Exemplarymaterials are disclosed in U.S. Pat. No. 4,576,604 to Guittard et al.and U.S. Pat. No. 4,673,405 to Guittard et al., and U.S. Pat. No.6,004,582 to Faour et al. and the text Pharmaceutical Dosage Forms:Tablets Volume I, 2^(nd) Edition. (A. Lieberman. ed. 1989, MarcelDekker, Inc.), the relevant disclosures of which are hereby incorporatedby reference. In some embodiments, the rapidly dissolving coat will besoluble in saliva, gastric juices, or acidic fluids.

Materials which are suitable for making the water soluble and/orerodible coatings of the invention include, by way of example andwithout limitation, water soluble polysaccharide gums such ascarrageenan, fucoidan, gum ghatti, tragacanth, arabinogalactan, pectin,and xanthan; water-soluble salts of polysaccharide gums such as sodiumalginate, sodium tragacanthin, and sodium gum ghattate; water-solublehydroxyalkylcellulose wherein the alkyl member is straight or branchedof 1 to 7 carbons such as hydroxymethylcellulose, hydroxyethylcellulose,and hydroxypropylcellulose; synthetic water-soluble cellulose-basedlamina formers such as methyl cellulose and its hydroxyalkylmethylcellulose derivatives such as a member selected from the groupconsisting of hydroxyethyl methylcellulose, hydroxypropylmethylcellulose, and hydroxybutyl methylcellulose; croscarmellosesodium; other cellulose polymers such as sodium carboxymethylcellulose;and other materials known to those of ordinary skill in the art. Otherlamina forming materials that can be used for this purpose includepoly(vinylpyrrolidone), polyvinylalcohol, polyethylene oxide, a blend ofgelatin and polyvinyl-pyrrolidone, gelatin, glucose, saccharides,povidone, copovidone, poly(vinylpyrrolidone)-poly(vinyl acetate)copolymer. The water soluble coating can comprise other pharmaceuticalexcipients that do or do not alter the way in which the water solublecoating behaves. The artisan of ordinary skill will recognize that theabove-noted materials include film-forming polymers.

Other materials which can be used in the water soluble and/or erodiblecoatings include hydroxypropylcellulose, microcrystalline cellulose(MCC, Avicel™ from FMC Corp.), poly(ethylene-vinyl acetate) (60:40)copolymer (EVAC from Aldrich Chemical Co.), 2-hydroxyethylmethacrylate(HEMA), MMA, terpolymers of HEMA:MMA:MA synthesized in the presence ofN,N′-bis(methacryloyloxyethyloxycarbonylamino)-azobenzene, azopolymers,enteric coated timed release system (Time Clock® from PharmaceuticalProfiles, Ltd., UK) and calcium pectinate can be included in the watersoluble coat.

The inert water soluble and/or erodible coat covering the semipermeablewall and blocking the passageway is made of synthetic or naturalmaterial that, through selective dissolution or erosion, allows thepassageway to become unblocked thus allowing the process of osmoticdelivery to start. This slow or fast dissolving water soluble coat canbe impermeable to a first external fluid, while being soluble in asecond external fluid. This property can help to achieve a controlledand selective release of the active compound in the nucleus.

In some embodiments, the inert water soluble and/or erodible coat willbe insoluble in the fluid of a first environment of use, such as gastricjuices, acidic fluids, or polar liquids, and soluble or erodible in thefluid of a second environment of use, such as intestinal juices,substantially pH neutral or basic fluids, or apolar liquids. A widevariety of other polymeric materials are known to possess these varioussolubility properties and can be included in the water soluble coat.Such other polymeric materials include, by way of example and withoutlimitation, cellulose acetate phthalate (CAP), cellulose acetatetrimelletate (CAT), poly(vinyl acetate)phthalate (PVAP), hydroxypropylmethylcellulose phthalate (HP), poly(methacrylate ethylacrylate) (1:1)copolymer (MA-EA), poly(methacrylate methylmethacrylate) (1:1) copolymer(MA-MMA), poly(methacrylate methylmethacrylate) (1:2) copolymer,Eudragit™ L-30-D (MA-EA, 1:1), Eudragit™ L-100-55 (MA-EA, 1:1),hydroxypropyl methylcellulose acetate succinate (HPMCAS), Coateric™(PVAP), Aquateric™ (CAP), AQOAT™ (HPMCAS) and combinations thereof. Thewater-soluble coat can also comprise dissolution aids, stabilitymodifiers, and bioabsorption enhancers.

An optional polymeric material for use in the inert water soluble and/orerodible coat includes enteric materials that resist the action ofgastric fluid avoiding permeation through the semipermeable wall whileone or more of the materials in the core are solubilized in theintestinal tract thereby allowing delivery of a drug in the core byosmotic pumping to begin. A material that easily adapts to this kind ofrequirement is a poly(vinylpyrrolidone)-vinyl acetate copolymer, such asthe material supplied by BASF under its Kollidon VA64™, mixed withmagnesium stearate and other similar excipients. The water solubleand/or erodible coat can also comprise povidone, which is supplied byBASF under its Kollidon K 30™, and hydroxypropyl methylcellulose, whichis supplied by Dow under its Methocel E-15™. The materials can beprepared in solutions having different concentrations of polymeraccording to the desired solution viscosity. For example, a 10% p/vaqueous solution of Kollidon™ K 30 has a viscosity of about 5.5-8.5 cpsat 20° C., and a 2% p/v aqueous solution of Methocel™ E-15 has aviscosity of about 13-18 cps at 20° C.

The inert water soluble and/or erodible coat can also comprise othermaterials suitable which are substantially resistant to gastric juicesand which will promote either enteric or colonic release. For thispurpose, the inert water soluble and/or erodible coat can comprise oneor more materials that do not dissolve, disintegrate, or change theirstructure in the stomach and during the period of time that the osmoticdevice resides in the stomach. Representative materials that keep theirintegrity in the stomach can comprise a member selected from the groupconsisting of (a) keratin, keratin sandarac-tolu, salol (phenylsalicylate), salol beta-naphthylbenzoate and acetotannin, salol withbalsam of Peru, salol with tolu, salol with gum mastic, salol andstearic acid, and salol and shellac; (b) a member selected from thegroup consisting of formalized protein, formalized gelatin, andformalized cross-linked gelatin and exchange resins; (c) a memberselected from the group consisting of myristic acid-hydrogenated castoroil-cholesterol, stearic acid-mutton tallow, stearic acid-balsam oftolu, and stearic acid-castor oil; (d) a member selected from the groupconsisting of shellac, ammoniated shellac, ammoniated shellac-salol,shellac-wool fat, shellac-acetyl alcohol, shellac-stearic acid-balsam oftolu, and shellac n-butyl stearate; (e) a member selected from the groupconsisting of abietic acid, methyl abietate, benzoin, balsam of tolu,sandarac, mastic with tolu, and mastic with acetyl alcohol; (f) acrylicresins represented by anionic polymers synthesized from methacrylic acidand methacrylic acid methyl ester, copolymeric acrylic resins ofmethacrylic and methacrylic acid and methacrylic acid alkyl esters,copolymers of alkacrylic acid and alkacrylic acid alkyl esters, acrylicresins such asdimethylaminoethylmethacrylate-butylmethacrylate-methylmethacrylatecopolymer of 150,000 molecular weight, methacrylicacid-methylmethacrylate 50:50 copolymer of 135,000 molecular weight,methacrylic acid-methylmethacrylate 30:70-copolymer of 135,000 mol. wt.,methacrylic acid-dimethylaminoethyl-methacrylate-ethylacrylate copolymerof 750,000 mol. wt., methacrylic acid-methylmethacrylate-ethylacrylatecopolymer of 1,000,000 mol. wt., andethylacrylate-methylmethacrylate-ethylacrylate copolymer of 550,000 mol.wt; and, (g) an enteric composition comprising a member selected fromthe group consisting of cellulose acetyl phthalate, cellulose diacetylphthalate, cellulose triacetyl phthalate, cellulose acetate phthalate,hydroxypropyl methylcellulose phthalate, sodium cellulose acetatephthalate, cellulose ester phthalate, cellulose ether phthalate,methylcellulose phthalate, cellulose ester-ether phthalate,hydroxypropyl cellulose phthalate, alkali salts of cellulose acetatephthalate, alkaline earth salts of cellulose acetate phthalate, calciumsalt of cellulose acetate phthalate, ammonium salt of hydroxypropylmethylcellulose phthalate, cellulose acetate hexahydrophthalate,hydroxypropyl methylcellulose hexahydrophthalate, polyvinyl acetatephthalate diethyl phthalate, dibutyl phthalate, dialkyl phthalatewherein the alkyl comprises from 1 to 7 straight and branched alkylgroups, aryl phthalates, and other materials known to one or ordinaryskill in the art.

An alternative embodiment of the invention includes pore former(s) inthe wall to form additional passageways over time.

Release of active agent from the core can be delayed such that therelease profile of active agent will exhibit delayed and then controlledrelease. Such a device would be termed a delayed controlled releasedevice.

The osmotic device of the invention comprises at least one passageway(pore, hole, or aperture) that communicates the exterior of thesemipermeable wall with the core of the device. The passageway can beformed according to any of the known methods of forming passageways in asemipermeable membrane. Such methods include, for example, 1) drilling ahole through the semipermeable membrane with a bit or laser; 2)including a water soluble material within the composition that forms thesemipermeable membrane such that a pore forms when the osmotic device isin an aqueous environment of use; 3) punching a hole through thesemipermeable membrane; or 4) employing a tablet punch having a pin topunch a hole through the semipermeable lamina. The passageway can passthrough the semipermeable wall and one or more of any other laminacoated onto the semipermeable membrane or between the semipermeablemembrane and the core. The passageway(s) can be shaped as desired. Insome embodiments, the passageway is laser drilled and is shaped as anoval, ellipse, slot, slit, cross or circle.

Methods of forming passageways in semipermeable membranes of osmoticdevices are disclosed in U.S. Pat. No. 4,088,864 to Theeuwes et al.,U.S. Pat. No. 4,016,880 to Theeuwes et al., U.S. Pat. No. 3,916,899 toTheeuwes et al., U.S. Pat. No. 4,285,987 to Ayer et al., U.S. Pat. No.4,783,337 to Wong et al., U.S. Pat. No. 5,558,879 to Chen et al., U.S.Pat. No. 4,801,461 to Hamel et al., U.S. Pat. No. 3,845,770 to Theeuweset al., PCT International Publication No. WO 04/103349 to Faour, andU.S. Pat. No. 6,809,288 to Faour, the disclosures of which are herebyincorporated by reference.

The preformed passageway in the wall is typically generated bymechanical means, such as perforation by a laser or drill, or any othersimilar method known to those of ordinary skill in the art. Thepassageway is generally formed by controlled laser perforation, using anapparatus similar to that disclosed in Theeuwes et al. '864, the entiredisclosure of which is incorporated herein by reference. Specificembodiments of the controlled laser perforation method will varyaccording to the equipment used. The laser equipment of Theeuwes et al.'864 can be modified as described herein to prepare an osmotic deviceaccording to the invention. Other suitable laser equipment, and methodsof use thereof, are disclosed in Emerton et al. '793 and Roy '771, theentire disclosures of which are hereby incorporated by reference. Theprocess and system of Faour (U.S. Pregrant Patent Publication No.2002/0099361) can also be used to form the preformed passageway and/oretch in the wall.

A preformed passageway can be made to substantially retain its sizeduring use of the device or it can be made to increase in size duringuse of the dosage form. Preformed passageways of different sizes, shapesand functions can be used.

In one embodiment of the invention the preformed passageway in the wallmay dissolve or tear in a predetermined or random manner, and the shapeof the preformed passageway after enlargement can be made to approximatea predetermined or randomly determined shape. The extent to which apassageway increases in size can also be related to the viscosity,molecular weight or degree of substitution of the at least oneexcipient. Generally, increasing the viscosity, molecular weight, ordegree of substitution of the at least one excipient will increase theextent to which the passageway increases in size.

A device according to the present invention can comprise one or morepreformed passageways including two, three, four, five, six, seven,eight, nine, ten or more preformed passageways. It is only necessarythat the preformed passageways together are adapted to permit controlledrelease of ingredients from the core during use. In some embodiments,the membrane comprises one preformed passageway having a diameterranging from 0.2 mm to 0.8 mm. In other embodiments, the total area ofthe preformed passageway(s) present in the membrane ranges from 0.12 mm²to 2.1 mm².

The osmotic device of the invention can also comprise an adsorbent,antioxidant, buffering agent, colorant, flavorant, sweetening agent,antiadherent, binder, diluent, direct compression excipient,disintegrant, glidant, lubricant, opaquant and/or polishing agent.

As used herein, the term “adsorbent” is intended to mean an agentcapable of holding other molecules onto its surface by physical orchemical (chemisorption) means. Such compounds include, by way ofexample and without limitation, powdered and activated charcoal andother materials known to one of ordinary skill in the art.

As used herein, the term “antioxidant” is intended to mean an agent thatinhibits oxidation and thus is used to prevent the deterioration ofpreparations by the oxidative process. Such compounds include, by way ofexample and without limitation, ascorbic acid, ascorbyl palmitate,butylated hydroxyanisole, butylated hydroxytoluene, hypophosphorousacid, monothioglycerol, propyl gallate, sodium ascorbate, sodiumbisulfite, sodium formaldehyde sulfoxylate and sodium metabisulfite andother materials known to one of ordinary skill in the art.

As used herein, the term “buffering agent” is intended to mean acompound used to resist change in pH upon dilution or addition of acidor alkali. Such compounds include, by way of example and withoutlimitation, potassium metaphosphate, potassium phosphate, monobasicsodium acetate and sodium citrate anhydrous and dihydrate and othermaterials known to one of ordinary skill in the art.

As used herein, the term “sweetening agent” is intended to mean acompound used to impart sweetness to a preparation. Such compoundsinclude, by way of example and without limitation, aspartame, dextrose,glycerin, mannitol, saccharin sodium, sorbitol and sucrose and othermaterials known to one of ordinary skill in the art.

As used herein, the term “antiadherent” is intended to mean an agentthat prevents the sticking of tablet formulation ingredients to punchesand dies in a tableting machine during production. Such compoundsinclude, by way of example and without limitation, magnesium stearate,talc, calcium stearate, glyceryl behenate, PEG, hydrogenated vegetableoil, mineral oil, stearic acid and other materials known to one ofordinary skill in the art.

As used herein, the term “binder” is intended to mean a substance usedto cause adhesion of powder particles in granulations. Such compoundsinclude, by way of example and without limitation, acacia,poly(vinylpyrrolidone), compressible sugar (e.g., NuTab™),ethylcellulose, gelatin, liquid glucose, povidone, pregelatinizedstarch, tragacanth, starch, cellulose materials such as methyl celluloseand sodium carboxy methyl cellulose, alginic acids and salts thereof,polyethylene glycol, guar gum, polysaccharides, bentonites, sugars,invert sugars, poloxamers (PLURONIC™ F68, PLURONIC™ F127), collagen,albumin, cellulosics in nonaqueous solvents, combinations thereof andthe like.

Other binders include, for example, polypropylene glycol,polyoxyethylene-polypropylene copolymer, polyethylene ester,polyethylene sorbitan ester, polyethylene oxide, combinations thereofand other materials known to one of ordinary skill in the art.

As used herein, the term “diluent” or “filler” is intended to mean aninert substance used as filler to create the desired bulk, flowproperties, and compression characteristics in the preparation oftablets and capsules. Such compounds include, by way of example andwithout limitation, dibasic calcium phosphate, kaolin, lactose, sucrose,mannitol, microcrystalline cellulose, powdered cellulose, precipitatedcalcium carbonate, sorbitol, and starch and other materials known to oneof ordinary skill in the art.

As used herein, the term “direct compression excipient” is intended tomean a compound used in direct compression tablet formulations. Suchcompounds include, by way of example and without limitation, dibasiccalcium phosphate (e.g., Ditab) and other materials known to one ofordinary skill in the art.

As used herein, the term “glidant” is intended to mean agents used intablet and capsule formulations to promote the flowability of agranulation. Such compounds include, by way of example and withoutlimitation, colloidal silica, cornstarch, talc, calcium silicate,magnesium silicate, colloidal silicon, silicon hydrogel and othermaterials known to one of ordinary skill in the art.

As used herein, the term “lubricant” is intended to mean substances usedin tablet formulations to reduce friction during tablet compression.Such compounds include, by way of example and without limitation,calcium stearate, magnesium stearate, mineral oil, stearic acid, andzinc stearate and other materials known to one of ordinary skill in theart.

As used herein, the term “opaquant” is intended to mean a compound usedto render a capsule or a tablet coating opaque. May be used alone or incombination with a colorant. Such compounds include, by way of exampleand without limitation, titanium dioxide and other materials known toone of ordinary skill in the art.

As used herein, the term “polishing agent” is intended to mean acompound used to impart an attractive sheen to coated tablets. Suchcompounds include, by way of example and without limitation, carnaubawax, and white wax and other materials known to one of ordinary skill inthe art.

As used herein, the term “disintegrant” is intended to mean a compoundused in solid dosage forms to promote the disruption of the solid massinto smaller particles which are more readily dispersed or dissolved.Exemplary disintegrants include, by way of example and withoutlimitation, starches such as corn starch, potato starch, pre-gelatinizedand modified starches thereof, crospovidone (cross linked polyvinylpyrrolidone), sweeteners, clays, such as bentonite, microcrystallinecellulose (e.g., Avicel), carboxymethylcellulose calcium, cellulosepolyacrilin potassium (e.g., Amberlite), alginates, sodium starchglycolate, gums such as agar, guar, locust bean, karaya, pectin,tragacanth and other materials known to one of ordinary skill in theart.

As used herein, the term “colorant” is intended to mean a compound usedto impart color to solid (e.g., tablets) pharmaceutical preparations.Such compounds include, by way of example and without limitation, FD&CRed No. 3, FD&C Red No. 20, FD&C Yellow No. 6, FD&C Blue No. 2, D&CGreen No. 5, D&C Orange No. 5, D&C Red No. 8, caramel, and ferric oxidered, other F.D. & C. dyes and natural coloring agents such as grape skinextract, beet red powder, beta-carotene, annato, carmine, turmeric,paprika, and other materials known to one of ordinary skill in the art.The amount of coloring agent used will vary as desired.

As used herein, the term “flavorant” is intended to mean a compound usedto impart a pleasant flavor and often odor to a pharmaceuticalpreparation. Exemplary flavoring agents or flavorants include syntheticflavor oils and flavoring aromatics and/or natural oils, extracts fromplants, leaves, flowers, fruits and so forth and combinations thereof.These may also include cinnamon oil, oil of wintergreen, peppermintoils, clove oil, bay oil, anise oil, eucalyptus, thyme oil, cedar leaveoil, oil of nutmeg, oil of sage, oil of bitter almonds and cassia oil.Other useful flavors include vanilla, citrus oil, including lemon,orange, grape, lime and grapefruit, and fruit essences, including apple,pear, peach, strawberry, raspberry, cherry, plum, pineapple, apricot andso forth. Flavors which have been found to be particularly usefulinclude commercially available orange, grape, cherry and bubble gumflavors and mixtures thereof. The amount of flavoring may depend on anumber of factors, including the organoleptic effect desired. Flavorswill be present in any amount as desired by those of ordinary skill inthe art. Particularly preferred flavors are the grape and cherry flavorsand citrus flavors such as orange.

The present device can also employ one or more commonly known surfaceactive agents or cosolvents that improve wetting or disintegration ofthe osmotic device core or layers.

It is contemplated that the osmotic device of the invention can alsoinclude oils, for example, fixed oils, such as peanut oil, sesame oil,cottonseed oil, corn oil and olive oil; fatty acids, such as oleic acid,stearic acid and isotearic acid; and fatty acid esters, such as ethyloleate, isopropyl myristate, fatty acid glycerides and acetylated fattyacid glycerides. It can also be mixed with alcohols, such as ethanol,isopropanol, hexadecyl alcohol, glycerol and propylene glycol; withglycerol ketals, such as 2,2-dimethyl-1,3-dioxolane-4-methanol; withethers, such as poly(ethyleneglycol) 450, with petroleum hydrocarbons,such as mineral oil and petrolatum; with water, or with mixturesthereof; with or without the addition of a pharmaceutically suitablesurfactant, suspending agent or emulsifying agent.

Soaps and synthetic detergents may be employed as surfactants and asvehicles for detergent compositions. Suitable soaps include fatty acidalkali metal, ammonium, and triethanolamine salts. Suitable detergentsinclude cationic detergents, for example, dimethyl dialkyl ammoniumhalides, alkyl pyridinium halides, and alkylamine acetates; anionicdetergents, for example, alkyl, aryl and olefin sulfonates, alkyl,olefin, ether and monoglyceride sulfates, and sulfosuccinates; nonionicdetergents, for example, fatty amine oxides, fatty acid alkanolamides,and poly(oxyethylene)-block-poly(oxypropylene) copolymers; andamphoteric detergents, for example, alkyl aminopropionates and2-alkylimidazoline quaternary ammonium salts; and mixtures thereof.

Various other components, not otherwise listed above, can be added tothe present formulation for optimization of a desired active agentrelease profile including, by way of example and without limitation,glycerylmonostearate, nylon, cellulose acetate butyrate, d,l-poly(lacticacid), 1,6-hexanediamine, diethylenetriamine, starches, derivatizedstarches, acetylated monoglycerides, gelatin coacervates,poly(styrene-maleic acid) copolymer, glycowax, castor wax, stearylalcohol, glycerol palmitostearate, poly(ethylene), poly(vinyl acetate),poly(vinyl chloride), 1,3-butylene-glycoldimethacrylate,ethyleneglycol-dimethacrylate and methacrylate hydrogels.

It should be understood, that compounds used in the art ofpharmaceutical formulation generally serve a variety of functions orpurposes. Thus, if a compound named herein is mentioned only once or isused to define more than one term herein, its purpose or function shouldnot be construed as being limited solely to that named purpose(s) orfunction(s).

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

A water insoluble active agent such as lercanidipine is primarilyreleased as insoluble particles, which therefore have limitedbioavailability. The concentration of dissolved lercanidipine may betemporarily improved sufficiently to improve absorption through one ormore of the following methods: a) delivery of solubilizers such assurfactants, citrate esters, and organic acids, b) increasingdissolution rate by utilizing lercanidipine that have a reduced particlesize, c) by co-delivery of a concentration-enhancing polymer, or d)combinations thereof. Examples of the surfactants include non-ionicand/or anionic surfactants, such as Tween 20, Tween 60 or Tween 80,polyoxyethylene or polyethylene-containing surfactants, or other longchain anionic surfactants, particularly sodium lauryl sulfate. Examplesof citrate ester derivatives are the alkyl esters, such as triethylcitrate. The use of a highly soluble organic acid as solubilizer servesmultiple purposes: it improves the solubility of lercanidipine,particularly when the use environment is at a pH above about 5 to 6; itprovides an osmotic pressure differential; it makes thelercanidipine-containing composition more hydrophilic so that it readilywets; and it acts as a fluidizing agent, lowering the viscosity of thelercanidipine-containing composition rapidly. Examples of organic acidsolubilizers include adipic acid, citric acid, fumaric acid, tartaricacid, succinic acid, and the like.

Example 1 discloses four lercanidipine II osmotic device formulationsdiffering only in the amount of citric acid, lots A, B, C, and D contain0%, 2.5%, 5.3%, and 10.5% of citric acid respectively. The lercanidipineis present as the hydrochloride salt Form II polymorph. FIG. 1 showsthat the osmotic device formulations containing citric acid provide afaster and higher release amount of lercanidipine (lots B, C, and D)than the osmotic device without citric acid (lot A). The in vitrotesting for lots A, B, C, and D was performed with USP Type IIdissolution apparatus (paddles), in 900 ml of water with 0.3%polysorbate 80, with a fixed agitation rate of 100 revolutions perminute, maintained at a temperature of 37±0.5° C. The samples weretested by high pressure liquid chromatography.

The release profiles obtained for six tablets (#1-#6) of the formulationcontaining 0% of citric acid (lot A) are disclosed in the table below,which detail the amount of lercanidipine released at the indicated timepoints, based upon when the osmotic device was exposed to the releaseliquid medium.

Released % Range (%) Time (hrs) #1 #2 #3 #4 #5 #6 Mean (%) SD (%) MinMax 0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 1 0.0 0.0 0.0 0.0 0.0 0.00.0 0.0 0.0 0.0 3 1.0 0.0 0.0 0.6 0.9 0.0 0.4 0.5 0.0 1.0 6 19.6 12.212.3 10.9 14.4 9.4 13.1 3.6 9.4 19.6 9 41.1 39.2 33.1 31.3 39.8 27.735.4 5.4 27.7 41.1 12 55.0 60.0 46.7 49.6 63.8 44.1 53.2 7.8 44.1 63.815 65.1 69.2 61.0 60.1 76.7 57.9 65.0 7.0 57.9 76.7 24 67.3 67.3 62.166.8 77.3 62.9 67.3 5.4 62.1 77.3

The release profiles obtained for six tablets (#1-#6) of the formulationcontaining 2.5% of citric acid (lot B) are disclosed in the table below,which detail the amount of lercanidipine released at the indicated timepoints, based upon when the osmotic device was exposed to the releaseliquid medium.

Released % Range (%) Time (hrs) #1 #2 #3 #4 #5 #6 Mean (%) SD (%) MinMax 0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 1 0.2 0.1 0.1 0.2 0.3 1.10.3 0.4 0.1 1.1 3 15.2 8.1 14.8 17.3 18.5 19.3 15.5 4.0 8.1 19.3 6 42.132.7 48.9 39.3 42.3 46.1 41.9 5.6 32.7 48.9 9 66.5 52.8 71.7 51.3 55.166.7 60.7 8.6 51.3 71.7 12 77.7 69.1 76.8 69.1 68.2 72.6 72.2 4.1 68.277.7 15 82.9 75.3 79.5 72.1 70.7 72.7 75.5 4.8 70.7 82.9 24 82.8 80.071.1 72.2 70.6 74.0 75.1 5.1 70.6 82.8

The release profiles obtained for six tablets (#1-#6) of the formulationcontaining 5.3% of citric acid (lot C) are disclosed in the table below,which detail the amount of lercanidipine released at the indicated timepoints, based upon when the osmotic device was exposed to the releaseliquid medium.

Released % Range (%) Time (hrs) #1 #2 #3 #4 #5 #6 Mean (%) SD (%) MinMax 0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 1 2.0 0.5 1.4 1.0 1.3 1.01.2 0.5 0.5 2.0 3 15.3 11.6 11.0 14.0 13.9 15.1 13.5 1.8 11.0 15.3 635.5 37.1 34.1 33.4 38.3 40.6 36.5 2.7 33.4 40.6 9 61.3 60.5 57.2 54.662.2 63.2 59.8 3.3 54.6 63.2 12 75.7 75.5 74.6 71.7 74.7 76.1 74.7 1.671.7 76.1 15 84.1 80.2 77.6 78.5 75.4 81.3 79.5 3.0 75.4 84.1 24 85.379.5 76.9 81.5 72.7 82.0 79.6 4.4 72.7 85.3

The release profiles obtained for six tablets (#1-#6) of the formulationcontaining 10% of citric acid (lot D) are disclosed in the table below,which detail the amount of lercanidipine released at the indicated timepoints, based upon when the osmotic device was exposed to the releaseliquid medium.

Released % Range (%) Time (hrs) #1 #2 #3 #4 #5 #6 Mean (%) SD (%) MinMax 0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 1 1.7 1.8 1.1 0.5 0.9 0.71.1 0.5 0.5 1.8 3 13.4 18.9 13.0 8.4 14.0 12.0 13.3 3.4 8.4 18.9 6 41.750.0 44.0 36.1 40.6 45.2 43.0 4.7 36.1 50.0 9 69.5 70.8 65.6 64.1 60.069.3 66.6 4.1 60.0 70.8 12 87.4 77.6 78.2 74.0 64.8 79.4 76.9 7.4 64.887.4 15 88.3 81.7 86.4 78.5 65.1 81.1 80.2 8.2 65.1 88.3 24 89.6 80.486.4 81.3 62.9 78.9 79.9 9.3 62.9 89.6

Tartaric acid has a significant destabilizing effect on the stability oflercanidipine hydrochloride as shown in Example 2 by the high amount ofimpurities generated (5.83% at 50° C. and 75% RH). Citric acid has verymild destabilizing effect on the stability of lercanidipinehydrochloride (1.24% at 50° C. and 75% RH) and it provides a faster andhigher release amount of lercanidipine than an osmotic device withoutcitric acid, as shown in FIG. 1. The results indicate that citric acidis a performance-enhancing acid, since it enhances the in vitrodissolution of lercanidipine as compared to tartaric acid and it has amuch lower destabilizing effect on lercanidipine than does tartaricacid.

The performance-enhancing acid can be present in different amounts inthe controlled release dosage form of the invention. It may providedifferent levels of performance enhancement, of the controlled releasedosage form, depending upon the amount that is included in the dosageform, e.g. the core of the dosage form. The performance-enhancing acidcan be present in the core in an amount of greater than 0% wt. up toabout 2.5% wt., 5% wt., 10% wt. or 15% wt. based upon the weight of theuncoated core. Accordingly, the weight ratio of lercanidipine toperformance-enhancing acid in the core may vary and can be optimized toprovide the desired level of enhancement in performance of the dosageform.

The predicted release profiles of the osmotic device formulationscontaining lercanidipine (30 mg strength) in the core and lercanidipine(10 mg strength) in an immediate or rapid release externaldrug-containing coat of Example 5 are disclosed in the table below.

Time Range (%) (hrs) Max Min 0 0 0 0.5 15 21 1 18 26 3 20 31 9 43 66 1562 86 24 78 100

FIG. 2 shows the predicted release profiles of the osmotic deviceformulations containing lercanidipine (30 mg strength) in the core andlercanidipine (10 mg strength) in an immediate or rapid release externaldrug-containing coat disclosed in Example 5.

The predicted release profiles of the osmotic device formulationscontaining lercanidipine (50 mg strength) in the core and lercanidipine(10 mg strength) in an immediate or rapid release externaldrug-containing coat of Example 5 are disclosed in the table below.

Time Range (%) (hrs) Min Max 0 0 0 0.5 10 14 1 12 18 3 14 24 9 40 63 1560 84 24 79 100

FIG. 3 shows the predicted release profiles of the osmotic deviceformulations containing lercanidipine (50 mg strength) in the core andlercanidipine (10 mg strength) in an immediate or rapid release externaldrug-containing coat disclosed in Example 5.

Example 6 discloses lercanidipine I osmotic device formulationsdiffering only in the acidifying agent used. The in vitro testing wasperformed with USP Type II dissolution apparatus (paddles), in 900 ml ofwater with 0.3% polysorbate 80, with a fixed agitation rate of 100revolutions per minute, maintained at a temperature of 37±0.5° C. Thesamples were tested by high pressure liquid chromatography.

The release profiles obtained for four tablets (#1-#4) of theformulation without acidifying agent are disclosed in the table below,which detail the amount of lercanidipine released at the indicated timepoints, based upon when the osmotic device was exposed to the releaseliquid medium.

Time Released % Mean SD Range (%) (hrs) #1 #2 #3 #4 (%) (%) Min Max 00.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 1 0.2 0.2 0.2 0.2 0.2 0.0 0.2 0.2 3 2.93.6 0.6 4.4 2.9 1.6 0.6 4.4 6 17.6 24.3 2.8 18.5 15.8 9.1 2.8 24.3 937.7 46.7 43.7 36.1 41.0 5.0 36.1 46.7 12 53.0 59.2 59.2 49.5 55.2 4.849.5 59.2 15 64.8 67.0 67.4 59.1 64.6 3.8 59.1 67.4 24 71.1 70.1 68.167.4 69.2 1.7 67.4 71.1

The release profiles obtained for six tablets (#1-#6) of the formulationcontaining fumaric acid as acidifying agent are disclosed in the tablebelow, which detail the amount of lercanidipine released at theindicated time points, based upon when the osmotic device was exposed tothe release liquid medium.

Released % Range (%) Time (hrs) #1 #2 #3 #4 #5 #6 Mean (%) SD (%) MinMax 0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 1 0.0 0.0 0.0 0.0 0.0 0.00.0 0.0 0.0 0.0 3 13.2 9.6 8.3 6.7 10.5 8.4 9.5 2.2 6.7 13.2 6 29.0 24.324.5 25.2 22.1 30.0 25.9 3.0 22.1 30.0 9 53.3 50.9 43.8 51.8 43.8 55.749.9 5.0 43.8 55.7 12 71.1 65.9 62.5 69.3 65.2 74.2 68.0 4.3 62.5 74.215 74.4 74.6 71.2 72.0 76.4 81.1 75.0 3.5 71.2 81.1 24 72.9 84.6 76.072.7 77.3 90.6 79.0 7.1 72.7 90.6

The release profiles obtained for six tablets (#1-#6) of the formulationcontaining oxalic acid as acidifying agent are disclosed in the tablebelow, which detail the amount of lercanidipine released at theindicated time points, based upon when the osmotic device was exposed tothe release liquid medium.

Released % Range (%) Time (hrs) #1 #2 #3 #4 #5 #6 Mean (%) SD (%) MinMax 0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 1 0.1 0.1 0.1 0.1 0.1 0.10.1 0.0 0.1 0.1 3 10.6 7.8 8.4 5.5 5.0 8.1 7.6 2.1 5.0 10.6 6 32.1 25.529.1 27.5 27.1 30.8 28.7 2.5 25.5 32.1 9 56.9 52.0 50.7 48.8 51.5 54.452.4 2.9 48.8 56.9 12 67.8 65.2 64.2 62.9 63.4 64.6 64.7 1.7 62.9 67.815 68.3 73.8 71.0 69.1 65.3 66.4 69.0 3.1 65.3 73.8 24 68.5 75.1 77.772.9 65.6 67.6 71.2 4.7 65.6 77.7

The release profiles obtained for six tablets (#1-#6) of the formulationcontaining succinic acid as acidifying agent are disclosed in the tablebelow, which detail the amount of lercanidipine released at theindicated time points, based upon when the osmotic device was exposed tothe release liquid medium.

Released % Range (%) Time (hrs) #1 #2 #3 #4 #5 #6 Mean (%) SD (%) MinMax 0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 1 0.1 0.0 0.0 0.0 0.0 0.00.0 0.0 0.0 0.1 3 11.1 7.0 7.2 7.5 7.0 5.0 7.5 2.0 5.0 11.1 6 28.9 29.124.7 26.3 23.2 18.9 25.2 3.8 18.9 29.1 9 54.9 49.8 45.9 51.3 46.3 43.548.6 4.2 43.5 54.9 12 68.7 66.7 64.2 68.4 62.8 63.4 65.7 2.6 62.8 68.715 75.0 71.5 69.1 69.7 69.5 68.9 70.6 2.3 68.9 75.0 24 80.4 73.5 73.569.9 74.7 69.3 73.5 4.0 69.3 80.4

The release profiles obtained for four tablets (#1-#4) of theformulation containing tartaric acid as acidifying agent are disclosedin the table below, which detail the amount of lercanidipine released atthe indicated time points, based upon when the osmotic device wasexposed to the release liquid medium.

Time Released % Mean SD Range (%) (hrs) #1 #2 #3 #4 (%) (%) Min Max 00.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 1 2.2 1.9 0.8 1.2 1.5 0.6 0.8 2.2 3 5.70.5 3.8 3.5 3.4 2.1 0.5 5.7 6 30.8 11.9 21.5 24.4 22.1 7.9 11.9 30.8 956.6 34.5 46.1 53.0 47.5 9.8 34.5 56.6 12 74.5 55.1 64.0 73.1 66.7 9.055.1 74.5 15 83.4 67.9 76.2 80.6 77.0 6.8 67.9 83.4 24 84.8 71.0 75.779.4 77.7 5.8 71.0 84.8

The release profiles obtained for four tablets (#1-#4) of theformulation containing citric acid as acidifying agent are disclosed inthe table below, which detail the amount of lercanidipine released atthe indicated time points, based upon when the osmotic device wasexposed to the release liquid medium.

Time Released % Mean SD Range (%) (hrs) #1 #2 #3 #4 (%) (%) Min Max 00.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 1 0.4 0.6 0.4 0.4 0.5 0.1 0.4 0.6 3 5.53.4 8.6 9.6 6.8 2.8 3.4 9.6 6 22.6 24.9 29.5 34.4 27.8 5.2 22.6 34.4 942.9 49.1 54.7 59.7 51.6 7.3 42.9 59.7 12 57.9 63.7 69.9 73.4 66.2 6.857.9 73.4 15 64.6 72.8 74.6 79.1 72.8 6.1 64.6 79.1 24 82.1 82.6 81.381.0 81.8 0.7 81.0 82.6

Fumaric acid, oxalic acid and succinic acid do not have a destabilizingeffect on the stability of lercanidipine hydrochloride as shown inExample 2 by the low amount of impurities generated (0.18%, 0.21% and0.21% respectively at 50° C. and 75% RH). The results indicate thatfumaric acid, oxalic acid and succinic acid, which are dicarboxylicacids, are performance-enhancing acids, since they enhance the in vitrodissolution of lercanidipine as compared to a formulation excluding theperformance-enhancing acid and they exhibit reduced degradation oflercanidipine, as compared to a similar formulation containing ascorbicacid, citric acid, tartaric acid or malic acid which are alpha hydroxycarboxylic acids.

The expected values after single dose or at steady-state, as describedin Example 7, for an osmotic tablet following once daily oraladministration, are as follows 1) the mean value of the maximum plasmaconcentration (Cmax) of lercanidipine is ≦8 ng/mL, preferably ≦6 ng/mL;2) the mean value of minimum concentration (Cmin) of lercanidipine is≧0.5 ng/mL in a dosage interval, preferably ≧1.5 ng/mL; and 3) thelercanidipine plasma concentrations is >1 ng/mL at least over 12 hoursin a dosage interval, preferably >2 ng/mL.

Example 8 discloses two lercanidipine I osmotic device formulationscontaining lercanidipine (30 and 50 mg strength) in the core andlercanidipine (10 mg strength) in an immediate or rapid release externaldrug-containing coat.

The release profiles obtained for six tablets (#1-#6) of thelercanidipine formulation (30 mg strength) in the core and lercanidipine(10 mg strength) in an immediate or rapid release externaldrug-containing coat of Example 8 are disclosed in the table below,which detail the amount of lercanidipine released at the indicated timepoints, based upon when the osmotic device was exposed to the releaseliquid medium.

Released % Range (%) Time (hrs) #1 #2 #3 #4 #5 #6 Mean (%) SD (%) MinMax 0 0.0 0.0 0.0 0.0 0.0 0.0 0 0 0 0 0.5 16.0 17.0 19.5 16.5 20.0 17.818 1.5 16 20 1 19.3 21.4 21.8 21.9 25.4 22.0 22 1.6 19 25 3 19.6 24.423.1 27.4 30.2 26.0 25 2.8 20 30 9 44.5 51.8 47.8 61.0 64.2 56.8 54 6.745 64 15 65.2 69.8 66.5 78.3 87.4 74.0 74 8.1 65 87 24 78.5 88.5 84.593.3 99.6 91.3 89 5.6 79 100

The release profiles obtained for six tablets (#1-#6) of thelercanidipine formulation (50 mg strength) in the core and lercanidipine(10 mg strength) in an immediate or rapid release externaldrug-containing coat of Example 8 are disclosed in the table below,which detail the amount of lercanidipine released at the indicated timepoints, based upon when the osmotic device was exposed to the releaseliquid medium.

Released % Range (%) Time (hrs) #1 #2 #3 #4 #5 #6 Mean (%) SD (%) MinMax 0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.5 11.0 11.3 13.0 11.513.4 11.8 12.0 0.9 11.0 13.4 1 12.9 14.4 14.7 14.8 17.5 14.8 14.9 1.312.9 17.5 3 13.1 17.8 16.1 21.0 22.8 19.3 18.3 2.6 13.1 22.8 9 41.8 48.243.5 58.3 63.5 53.5 51.5 7.9 41.8 63.5 15 60.1 68.2 64.3 77.5 82.5 72.770.9 7.2 60.1 82.5 24 79.8 89.0 84.3 94.2 99.8 91.8 89.8 5.8 79.8 99.8

One or more of the following drugs can be used in combination withlercanidipine in the dosage form: 1) a drug selected from the groupconsisting of an angiotensin converting enzyme inhibitor, an angiotensinII receptor blocker, a β-blocker, an α-blocker, a diuretic, and mixturesthereof; 2) an angiotensin converting enzyme inhibitor selected from thegroup consisting of enalapril, captopril, lisinopril, benazepril,enalaprilat, espirapril, fosinopril, moexipril, quinapril, ramipril,perindopril, and trandolapril; 3) an angiotensin II receptor blockerselected from the group consisting of olmesartan, irbesartan, valsartan,telmisartan, losartan and eprosartan; 4) a β-blocker selected from thegroup consisting of carvedilol, pindolol, propranolol, practolol,metoprolol, esmolol, oxprenolol, timolol, atenolol, alprenolol, sotalol,carteolol, nadolol, betaxolol, penbutolol, acebutolol, and bisoprolol;5) an α-blocker selected from the group consisting of doxazosin,prazosin, terazosin, and labetalol; 6) enalapril maleate; 7) enalaprilmaleate and hydrochlorothiazide; 8) lisinopril; 9) lisinopril andhydrochlorothiazide; 10) olmersartan; 11) olmersartan andhydrochlorothiazide; 12) irbesartan; 13) irbesartan andhydrochlorothiazide; 14) carvedilol; 15) carvedilol andhydrochlorothiazide; 16) doxazosin; 17) doxazosin andhydrochlorothiazide; and 18) a diuretic selected from the groupconsisting of chlorothiazide, acetazolamide, methazolamide, triamterene,furosemide, indapamide, flumethiazide, bumetanide, ethacrynic acid,torsemide, muzolimide, azosemide, piretanide, tripamide,hydrochlorothiazide, chlorthalidone, indapamide, metozalone,cyclopenthiazide, amiloride, xipamide, mefruside, dorzolamide,ethoxzolamide, cyclothiazide, clopamide, dichlorphenamide,hydroflumethiazide, trichlormethiazide, polythiazide and benzothiazide.Such drug combinations can be used to treat a disease or disorder thatis therapeutically responsive to lercanidipine and/or the other drug(s)included in the dosage form.

Unless otherwise specified, the term lercanidipine is taken to mean thefree base or salt form thereof or a combination thereof. It can bepresent in the hydrate, solvate, anhydrous or oil form or a combinationthereof. Lercanidipine can be present in amorphous or crystalline formor a combination thereof. In crystalline form, any polymorph orcombination of two or more different polymorphs of lercanidipine can bepresent. Lercanidipine can be present in racemic, optically enriched(for either the R or S enantiomer), optically pure form. Combinations ofthese various forms of lercanidipine can be employed in the controlledrelease dosage form, osmotic device, of the invention.

The following examples should not be considered exhaustive, but merelyillustrative of only a few of the many embodiments contemplated by thepresent invention. The methods described herein can be followed toprepare osmotic devices according to the invention.

EXAMPLE 1

Lercanidipine HCl polymorph II osmotic device tablets of 30 mg strengthswere manufactured as described herein. The osmotic device tabletscontain the following ingredients in the amounts indicated.

Excipients Lot A Lot B Lot C Lot D Core Lercanidipine II 30 30 30 30Surfactant 1.3 1.3 1.3 1.3 Osmotic agent 100 100 100 100 Binder 22.722.7 22.7 22.7 Filler 50 43.2 35.2 20.2 Water swellable polymer 1 68.468.2 68.2 68.2 Water swellable polymer 2 5.7 5.7 5.7 5.7 Glidant 3.3 3.33.3 3.3 Lubricant 3.6 3.6 3.6 3.6 Citric acid 0 7 15 30 Core weight 285285 285 285 Membrane Cellulose ester 1 28.45 28.45 28.45 28.45 Celluloseester 2 23.8 23.8 23.8 23.8 Plasticizer 2.75 2.75 2.75 2.75 Membraneweight 35 35 35 35

First, the core composition is prepared by placing lercanidipinehydrochloride, one water swellable polymer 1, a diluent, an osmoticagent, citric acid, the 50% of the glidant, and a binder in a high shearmixer and mix for 5 minutes. Then a water swellable polymer 2 is addedand mixed for 1 minute more. The granulation process is initiated by thegradual addition of a granulating solution containing a surfactant andpurified water to the high shear with continuous blending to produce awet blend. Next, the wet blend is granulated and dried at 40-50° C. for20 minutes in a static bed to remove the water. Then, the dry granulesare screened through a 16 USP mesh screen for size reduction. Next, thescreened granules are mixed with the 50% remaining of the glidant and alubricant, that have been previously passed through a 40 mesh screen, ina V-Blender during 5 minutes. This final blend is tableted to providethe cores.

A first composition to cover the cores is prepared as follows: twocellulose esters and a plasticizer are added to organic solvent andpurified water, and mixed thoroughly to form a polymer solution. Thissolution is sprayed onto the tablets in a perforated pan coater to formfilm-coated cores. A 0.5 mm hole is drilled through the coating toprovide perforated film-coated tablets.

EXAMPLE 2

Samples of lercanidipine/tartaric acid in a 1/1 ratio andlercanidipine/citric acid in a 1/1 ratio were prepared. One set ofsamples was stored in clear glass vials with butyl caps and aluminumseals and kept for 1.5 month at 50° C. A second set was put into vialsand the butyl cap were replaced by gauze and exposed to 50° C.+75% RHwhile a third set of samples was maintained at 5° C. in refrigerator asreference condition. Analytical testing of the different samples wasdone by HPLC, column RP18, 300×3.9 mm ID, particle size 4 μm, inacetonitrile-0.15 M sodium perchlorate buffer, pH 3.0, at a flow rate of1.3 ml/min, at 30° C., detector UV 240 nm. In all cases impurities werereported as % of the area of the impurity peak referred to the area ofthe main peak (a/a). The lercanidipine is the lercanidipine HClpolymorph II.

Lercanidipine/ Lercanidipine/ Lercanidipine Tartaric Acid Citric AcidType of Impurity 50° C. + 50° C. + 50° C. + (% a/a) 5° C. 50° C. 75% RH5° C. 50° C. 75% RH 5° C. 50° C. 75% RH Impurity B 0.02 0.01 0.01 0.010.01 0.09 0.01 0.01 0.22 Impurity 3 0.18 0.22 0.28 0.05 0.09 4.85 0.060.10 0.50 Maximum nd 0.03 0.05 0.01 0.03 0.77 0.12 nd 0.26 unknownimpurities Total impurities 0.20 0.31 0.43 0.08 0.14 5.83 0.22 0.11 1.24

EXAMPLE 3

An open label, randomized, cross-over, single-dose study of four periodsis carried out according to Williams design with four formulations,three new lercanidipine 30 mg osmotic device formulations versus themarketed immediate release formulation Zanidip® 20 mg tablet (RecordatiS.p.A., Italy). Twenty healthy male and female volunteers, from 45 to 65years of age, will be given consecutive numbers from 1 to 20 accordingto the time they begin the study. Subjects will receive the 4 treatmentsduring the study, with a washout period of at least 5 days in-between.The lercanidipine will be administered after an overnight fast, lastingal least 10 hours. Anamnesis, physical examination, vital signs,laboratory tests, ECG and adverse events recording will be performed.Treatment sequence will be assigned by randomization and thus eachvolunteer will receive any of the treatments under study in the firstperiod, and the remaining in periods 2, 3 and 4 according to theallotted sequence. The evaluation of the plasma concentrations oflercanidipine will be at the following times after dose administration:0 hours (preceding drug administration), 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8,10, 12, 14, 16, 20, 24 and 28 hours post-dose. The time of drugadministration will be defined as study time Oh. The concentrations oflercanidipine in plasma will be determined by means of a validatedLC-MS/MS method. The lower limit of quantification will be 0.1 ng/mL.

The preformed statistical analyses will be descriptive statistics onvital signs and PK parameters, ANOVA on log-transformed C_(max),AUC_(t), AUC_(∞), mean ratio (test/reference) and 90% confidenceintervals for C_(max), AUC_(t) and AUC_(∞) and C₂₄ (not transformedvalues), and non-parametric 90% confidence intervals for t_(max) mediandifferences.

EXAMPLE 4

Samples of lercardinidine/malic acid, lercarnidipine/ascorbic acid,lercanidipine/fumaric acid, lercanidipine/oxalic acid, andlercanidipine/succinic acid, each in a 1/1 ratio, were treated asdescribed in example 2. The lercanidipine is the lercanidipine HClpolymorph II.

Type of Impurity 50° C. + 50° C. + 50° C. + (% a/a) 5° C. 50° C. 75% RH5° C. 50° C. 75% RH 5° C. 50° C. 75% RH Lercanidipine/ Lercanidipine/Lercanidipine Malic Acid Ascorbic Acid Impurity B 0.01 0.01 0.01 nd nd0.25 0.03 0.02 0.01 Impurity 3 0.27 0.30 0.16 0.02 0.10 14.26 0.22 0.140.22 Maximum 0.04 0.04 0.04 0.04 0.04 1.22 0.04 0.04 0.05 unknownimpurities Total impurities 0.45 0.47 0.34 0.15 0.24 23.37 0.44 0.330.43 Lercanidipine/ Lercanidipine/ Lercanidipine/ Fumaric Acid OxalicAcid Succinic Acid Impurity B nd 0.01 0.00 nd nd 0.01 0.01 0.01 0.01Impurity 3 0.05 0.07 0.05 0.03 0.06 0.06 0.03 0.03 0.05 Maximum 0.040.06 0.04 0.04 0.04 0.04 0.04 0.04 0.04 unknown impurity Totalimpurities 0.19 0.27 0.18 0.17 0.29 0.21 0.17 0.19 0.21

EXAMPLE 5

The following procedure is used to prepare osmotic device formulationscontaining lercanidipine (30 and 50 mg strength) in the core andlercanidipine HCl (10 mg strength) in an immediate or rapid releaseexternal drug-containing coat. The osmotic device formulations containthe following ingredients in the amounts indicated:

Excipients/Functional category Amount (mg) Lercanidipine ER strength30.00 50.00 Lercanidipine IR/RR strength 10.00 10.00 Core LercanidipineHCl (Polymorph II) 30.00 50.00 Surfactant  1.00-30.00  2.00-50.00Diluent  6.00-30.00 10.00-50.00 Osmotic agent  60.00-140.00 95.00-240.00 Binder  1.50-30.00  3.00-40.00 Performance-enhancing acid 0.90-40.00  2.00-65.00 Osmopolymer 1  70.00-130.00 120.00-220.00Osmopolymer 2  0.00-40.00  0.00-70.00 Osmopolymer 3  0.00-40.00 0.00-70.00 Glidant  0.10-10.00  0.20-15.00 Lubricant  0.50-15.00 1.00-25.00 Purified water* 20.00-50.00 30.00-80.00 Coating A Celluloseester 1 10.00-20.00 17.00-33.00 Cellulose ester 2  0.00-17.00 0.00-28.00 Plasticizer 1.00-2.00 1.70-3.30 Organic solvent*350.00-650.00  580.00-1080.00 Purified water*  60.00-130.00100.00-220.00 Coating B (optional) Water soluble polymer 0.60-3.001.00-5.00 Opaquant 0.60-3.00 1.00-5.00 Talc 3.00-9.00  5.00-15.00Purified water*  65.50-115.00 105.00-190.00 Coating C Lercanidipine HCl(Polymorph II) 10.00 10.00 Film forming polymer 10.00-40.00 10.00-40.00Plasticizer 1.50-6.00 1.50-6.00 Disintegrant  4.00-15.00  4.00-15.00Glidant 0.25-1.00 0.25-1.00 Purified water*  250.00-1000.00 250.00-1000.00 Coating D Film forming polymer  7.00-14.00 10.00-20.00Plasticizer 0.07-3.50 0.10-5.00 Opaquant 0.70-3.50 1.00-5.00 Talc0.70-7.00  1.00-10.00 Purified water* 126.00-210.00 180.00-300.00*denotes a component used during manufacture of the osmotic device butwhich is substantially absent (present in an amount of less than about10% or less than 5% by wt.) in the final dosage form.

Diluent, osmopolymers 1 and 2, a half of the glidant and the binder arefirst individually screened using a Quadro Comil equipped with a 0.075inch screen. The osmotic agent and the performance-enhancing acid aremilled using a Fitz Mill equipped with a screen 0.033 inch. The previousingredients and the lercanidipine are placed in a high shear granulatorbowl and mixed during 5 minutes to obtain an homogenous powder blend.The osmopolymer 3 is individually screened using a Quadro Comil equippedwith a 0.075 inch screen, and then is added to the homogenous powderblend and mixed during 1 additional minute. The granulation process isinitiated by the gradual addition of the surfactant in purified water toform a solution that is then added to the homogenous powder blend inorder to obtain a consistent granulation end point. The wet granules aresieved through a Quadro Comil equipped with a 0.375 inch screen and thendried in a static bed oven for reducing the humidity content between1.0-2.5%. Next, the dry granules are milled using a Quadro Comilequipped with a 0.125 inch screen and then with a 0.045 screen in orderto reduced and homogenize particle size. Next, a mixture of the otherhalf of the glidant and the lubricant, previously sieved through a 0.017inch screen, is added and mixed for about 5 minutes to obtain the finalblend in a V blender. This final blend is compressed in a Rotary TabletPress with 9.25-11.00 mm diameter punches to obtain uncoated cores. Theaverage weight of the uncoated cores is approximately between 276 to 294mg for the 30 mg dose and between 460 to 490 mg for the 50 mg dose.

An osmotic coating (A) composition is prepared as follows: organicsolvent and purified water are charge into a suitable vessel. Undercontinuous stirring, cellulose esters 1 and 2 are added and stirredvigorously until dissolution is completed. The plasticizer is added andhomogenized. The mixture is sprayed onto the uncoated cores to obtaincoated cores. The membrane coating of each core is then perforated withlaser equipment to form at least one passageway of 0.2-0.8 mm throughthe semipermeable coat.

The second coating (B) is prepared by mixing the water soluble polymer,opaquant and talc in purified water. This polymer mixture is sprayedonto the tablets in a perforated pan coater to obtain film-coatedtablets which membrane coating weighs approximately 13 mg for the 30 mgdose and 21 mg for the 50 mg.

The third coating (C) is prepared by mixing the lercanidipine, theplasticizer, the film forming polymer, the glidant and the disintegrantin purified water to obtain an homogeneous suspension. This previousmixture is sprayed onto the tablets in a perforated pan coater or fluidbed dryer in order to obtain film-coated tablets which membrane coatingweighs 46 mg approximately for both strength.

A final coating composition (D) is prepared as follows: the plasticizer,the film forming polymer, the opaquant and the talc are mixed in water.This mixture is sprayed onto the tablets in a perforated pan coater toobtain film-coated tablets which membrane coating weighs approximately15 mg for the 30 mg dose and 24 mg for the 50 mg.

EXAMPLE 6

The following procedure was used to prepare osmotic device formulationscontaining lercanidipine and an acidifying agent. The osmotic deviceformulations contained the following ingredients in the amountsindicated:

Ingredient Amount (mg) Core Lercanidipine hydrochloride (Polymorph I)30.00 Polisorbate 20 (Tween 20) 1.30 Microcrystalline cellulose PH 10133.70 Sodium chloride 101.50 PVP K 30 22.70 Polyethylene oxide WSR 20568.20 Performance-enhancing acid** 15.00 Hydroxypropylmethylcellulose(2208) K 4 M 5.70 Coloidal silicon dioxide 3.30 Magnesium stearate 3.60Purified water* 285.00 Coating Cellulose acetate 320 S NF 31.00Cellulose acetate 398 10 NF 26.00 Polyethylene glycol 400 3.00 Acetone*1020.00 Purified water* 180.00 *denotes a component used duringmanufacture of the osmotic device but which is substantially absent(present in an amount of less than about 10% or less than 5% by wt.) inthe final dosage form. **The following performance-enhancing acids wereused to prepare five different formulations: oxalic acid, succinic acid,fumaric acid, citric acid and tartaric acid.

First, the core composition was prepared by placing lercanidipinehydrochloride, polyethylene oxide WSR 205, microcrystalline cellulose PH101, sodium chloride, a performance-enhancing acid, the 50% of colloidalsilicon dioxide, and PVP K 30 in a high shear mixer and mix for 5minutes. Then hydroxypropylmethylcellulose was added and mixed for 1minute more. The granulation process was initiated by the gradualaddition of a granulating solution containing Tween 20 and purifiedwater to the high shear with continuous blending to produce a wet blend.Next, the wet blend was granulated and dried at 40-50° C. for 20 minutesin a static bed to remove the water. Then, the dry granules werescreened through a 16 USP mesh screen for size reduction. Next, thescreened granules were mixed with the 50% remaining of the colloidalsilicon dioxide and magnesium stearate, that had been previously passedthrough a 40 mesh screen, in a V-Blender during 5 minutes. This finalblend was tableted to provide the cores.

A first composition to cover the cores was prepared as follows:cellulose acetate 320 S NF, cellulose acetate 398 10 NF and polyethyleneglycol 400 were added to acetone and purified water, and mixedthoroughly to form a polymer solution. This solution was sprayed ontothe tablets in a perforated pan coater to form film-coated cores. A 0.5mm hole was drilled through the coating to provide perforatedfilm-coated tablets.

EXAMPLE 7

An open label, randomized, cross-over, multi-dose study under fedcondition, three periods with two new formulations, lercanidipineosmotic device formulations of example 8 versus the marketed immediaterelease formulation Zanidip® 20 mg tablet (Recordati S.p.A., Italy) iscarried out. Healthy male and female volunteers, from 21 to 65 years ofage, are given consecutive numbers according to the time they begin thestudy. Subjects receive the 3 treatments during the study, with awashout period of at least 5 days in-between. Each new formulation isadministered once daily, with standardized breakfast after an overnightfast along seven days. Anamnesis, physical examination, vital signs,laboratory tests, ECG and adverse events recording is performed.Treatment sequence is assigned by randomization and thus each volunteerreceives any of the treatments under study in the first period, and theremaining in periods 2 and 3 according to the allotted sequence.

The evaluation of the plasma concentrations of lercanidipine areevaluated at sequential times after dose administration on the last dayof treatment administration. The concentrations of lercanidipine inplasma is determined by means of a validated LC-MS/MS method. The lowerlimit of quantification is 0.1 ng/mL.

The preformed statistical analyses are descriptive statistics on vitalsigns and PK parameters, ANOVA on log-transformed Css (Cmin and Cmax),AUCt, AUCinf, mean ratio (test/reference) and 90% confidence intervalsfor Css (Cmin and Cmax), AUCt and AUCinf (not transformed values).

EXAMPLE 8

The following procedure is used to prepare osmotic device formulationscontaining lercanidipine HCl (30 and 50 mg strength based uponlercanidipine) in the core and lercanidipine HCl (10 mg strength basedupon lercanidipine) in an immediate or rapid release externaldrug-containing coat. The osmotic device formulations contain thefollowing ingredients in the amounts indicated:

Ingredients Amount (mg) Lercanidipine ER strength 30.00 50.00Lercanidipine IR/RR strength 10.00 10.00 Core Lercanidipine HCl(Polymorph II) 30.00 50.00 Polysorbate 20 1.30 2.17 Microcrystallinecellulose 101 8.70 14.50 Sodium chloride 100.00 166.70Polyvinylpyrrolidone K 30 22.70 37.83 Fumaric acid 7.00 11.70Polyethylene oxide WSR 205 99.80 166.30 Hydroxypropylmethylcellulose 100LV 4.30 7.17 Hydroxypropylmethylcellulose K4M 4.30 7.17 Colloidalsilicon dioxide 3.30 5.50 Magnesium stearate 3.60 6.00 Purified water*34.20 56.40 Coating A Cellulose acetate 320 S 15.38 25.00 Celluloseacetate 398 10 NF 8.50 14.00 Polyethylene glycol 400 1.50 2.50 Acetone*510.00 830.00 Purified water* 90.00 160.00 Coating B (optional)Copolyvidone 3.00 5.00 Titanium Dioxide 2.90 4.80 Talc 6.30 10.40Purified water* 65.50 106.80 Coating C Lercanidipine HCl (Polymorph II)10.00 10.00 Hydroxypropylmethylcellulose 2910 24.00 24.00 Polyethyleneglycol 6000 3.50 3.50 Crospovidone 8.00 8.00 Colloidal silicon dioxide0.50 0.50 Purified water* 540.00 540.00 Coating D Copolyvidone 12.7520.00 Polyethylene glycol 400 0.75 1.20 Titanium dioxide 0.75 1.20 Talc0.75 1.20 Purified water* 126.00 200.00 *denotes a component used duringmanufacture of the osmotic device but which is substantially absent(present in an amount of less than about 10% or less than 5% by wt.) inthe final dosage form.

Microcrystalline cellulose 101, hydroxypropylmethylcellulose K4M andhydroxypropylmethylcellulose 100 LV, a half of the colloidal silicondioxide and the polyvinylpyrrolidone K 30 are first individuallyscreened using a Quadro Comil equipped with a 0.075 inch screen. Sodiumchloride and fumaric acid are milled using a Fitz Mill equipped with ascreen 0.033 inch. The previous ingredients and lercanidipine are placedin a high shear granulator bowl and mixed during 5 minutes to obtain anhomogenous powder blend. The polyethylene oxide WSR 205 is individuallyscreened using a Quadro Comil equipped with a 0.075 inch screen, andthen is added to the homogenous powder blend and mixed during 1additional minute. The granulation process is initiated by the gradualaddition of the Polysorbate 20 in purified water to form a solution thatis then added to the homogenous powder blend in order to obtain aconsistent granulation end point. The wet granules are sieved through aQuadro Comil equipped with a 0.375 inch screen and then dried in astatic bed oven for reducing the humidity content between 1.0-2.5%.Next, the dry granules are milled using a Quadro Comil equipped with a0.125 inch screen and then with a 0.045 screen in order to reduced andhomogenize particle size. Next, a mixture of the other half of thecolloidal silicon dioxide and the magnesium stearate, previously sievedthrough a 0.017 inch screen, is added and mixed for about 5 minutes toobtain the final blend in a V blender. This final blend is compressed ina Rotary Tablet Press with 9.25-11.00 mm diameter punches to obtainuncoated cores. The average weight of the uncoated cores isapproximately 280 mg for the 30 mg dose and approximately 475 mg for the50 mg dose.

An osmotic coating (A) composition is prepared as follows: acetone andpurified water are charge into a suitable vessel. Under continuousstirring, cellulose acetate 320 S and cellulose acetate 398 10 NF areadded and stirred vigorously until dissolution is completed.Polyethylene glycol 400 is added and homogenized. The mixture is sprayedonto the uncoated cores to obtain coated cores. The membrane coating ofeach core is then perforated with laser equipment to form at least onepassageway of 0.2-0.8 mm through the semipermeable coat.

The second coating (B) is prepared by mixing copolyvidone, titaniumdioxide and talc in purified water. This polymer mixture is sprayed ontothe tablets in a perforated pan coater to obtain film-coated tabletswhich membrane coating weighs approximately 13 mg for the 30 mg dose and21 mg for the 50 mg.

The third coating (C) is prepared by mixing lercanidipine, polyethyleneglycol 6000, hydroxypropylmethylcellulose 2910, colloidal silicondioxide and crospovidone in purified water to obtain an homogeneoussuspension. This previous mixture is sprayed onto the tablets in aperforated pan coater in order to obtain film-coated tablets whichmembrane coating weighs approximately 46 mg for both strength.

A final coating composition (D) is prepared as follows: polyethyleneglycol 400, copolyvidone, titanium dioxide and the talc are mixed inwater. This mixture is sprayed onto the tablets in a perforated pancoater to obtain film-coated tablets which membrane coating weighsapproximately 15 mg for the 30 mg dose and approximately 24 mg for the50 mg dose.

The above is a detailed description of particular embodiments of theinvention. It is recognized that departures from the disclosedembodiments may be made within the scope of the invention and thatobvious modifications will occur to a person skilled in the art. Thoseof skill in the art should, in light of the present disclosure,appreciate that many changes can be made in the specific embodimentswhich are disclosed herein and still obtain a like or similar resultwithout departing from the spirit and scope of the invention. All of theembodiments disclosed and claimed herein can be made and executedwithout undue experimentation in light of the present disclosure.

1. An osmotic device comprising: 1) a core comprising lercanidipine, ora pharmaceutically acceptable salt thereof, a performance-enhancingacid, and one or more other pharmaceutical excipients; and 2) a wallenveloping the core and comprising at least one preformed passageway,wherein the device provides a controlled release of lercanidipine over aperiod of 8-36 hours.
 2. The osmotic device of claim 1, wherein the corethereof comprises lercanidipine, or a pharmaceutically acceptable saltthereof, a performance-enhancing acid, an osmotic agent, and at leastone swelling polymer, and optionally one or more pharmaceuticalexcipients.
 3. The device of claim 1, wherein the osmotic deviceprovides an increased bioavailability of lercanidipine followingadministration of the osmotic device to a subject in need thereof ascompared to a control osmotic device excluding the performance-enhancingacid.
 4. The device of claim 1, wherein the osmotic device provides anincreased stability of lercanidipine in the osmotic device duringstorage as compared to a control osmotic device excluding theperformance-enhancing acid.
 5. The device of claim 1, wherein theosmotic device provides an increased rate of release of lercanidipineupon exposure of the device to an aqueous environment of use orfollowing administration to a subject in need thereof as compared to anotherwise similar (control) osmotic device excluding theperformance-enhancing acid.
 6. The device of claim 1, wherein theosmotic device provides an increase in the overall amount oflercanidipine released upon exposure of the device to an aqueousenvironment of use or following administration to a subject in needthereof as compared to an otherwise similar control osmotic deviceexcluding the performance-enhancing acid.
 7. The device of claim 1,wherein lercanidipine is present as a mineral acid salt and theperformance-enhancing acid is present as an organic acid.
 8. The deviceof claim 7, wherein the performance-enhancing acid comprises amonocarboxylic acid, dicarboxylic acid, tricarboxylic acid,hydroxy-carboxylic acid, hydroxy-dicarboxylic acid,hydroxy-tricarboxylic acid, nonaromatic organic acid, or a combinationthereof.
 9. The device of claim 7, wherein the mineral acid ishydrochloric acid and the performance-enhancing acid is a dicarboxylicacid.
 10. The device of claim 7, wherein the performance-enhancing acidis selected from the group comprising fumaric acid, oxalic acid, andsuccinic acid.
 11. The device of claim 1 comprising 30-60 mg oflercanidipine.
 12. The device of claim 1 further comprising an immediaterelease coating comprising lercanidipine external to the wall.
 13. Thedevice of claim 12, wherein the immediate release coating comprises 10mg of lercanidipine.
 14. The device of claim 1, wherein the wall is asemipermeable membrane.
 15. The device of claim 1 further comprising atleast one other pharmaceutically active agent.
 16. The device of claim15, wherein the at least one other pharmaceutically active agent isselected from the group consisting of an angiotensin converting enzymeinhibitor, an angiotensin II receptor blocker, a β-blocker, anα-blocker, a diuretic, and a combination thereof.
 17. The device ofclaim 16, wherein the angiotensin converting enzyme inhibitor isselected from the group consisting of enalapril, captopril, lisinopril,benazepril, enalaprilat, espirapril, fosinopril, moexipril, quinapril,ramipril, perindopril, and trandolapril.
 18. The device of claim 16,wherein the angiotensin II receptor blocker is selected from the groupconsisting of olmesartan, irbesartan, valsartan, telmisartan, losartanand eprosartan.
 19. The device of claim 16, wherein the β-blocker isselected from the group consisting of carvedilol, pindolol, propranolol,practolol, metoprolol, esmolol, oxprenolol, timolol, atenolol,alprenolol, sotalol, carteolol, nadolol, betaxolol, penbutolol,acebutolol, and bisoprolol.
 20. The device of claim 16, wherein theα-blocker is selected from the group consisting of doxazosin, prazosin,terazosin, and labetalol.
 21. The device of claim 16, wherein thediuretic is selected from the group consisting of chlorothiazide,acetazolamide, methazolamide, triamterene, furosemide, indapamide,flumethiazide, bumetanide, ethacrynic acid, torsemide, muzolimide,azosemide, piretanide, tripamide, hydrochlorothiazide, chlorthalidone,metozalone, cyclopenthiazide, amiloride, xipamide, mefruside,dorzolamide, ethoxzolamide, cyclothiazide, clopamide, dichlorphenamide,hydroflumethiazide, trichlormethiazide, polythiazide and benzothiazide.22. The device of claim 15, wherein the at least one otherpharmaceutically active agent is selected from the group consisting of:enalapril maleate; enalapril maleate and hydrochlorothiazide;lisinopril; lisinopril and hydrochlorothiazide; olmersartan; olmersartanand hydrochlorothiazide; irbesartan; irbesartan and hydrochlorothiazide;carvedilol; carvedilol and hydrochlorothiazide; doxazosin; and doxazosinand hydrochlorothiazide.
 23. The device according to claim 1, whereinthe lercanidipine is released from the core according to the followingapproximate release profile: Time Range (%) (hrs) Min Max 0 0 0 0.5 1521 1 18 26 3 20 31 9 43 66 15 62 86 24 78 100


24. The device according to claim 1, wherein the performance-enhancingacid is present in the range of about 2.5%-15% wt. based upon the weightof the uncoated core.
 25. The device according to claim 1 furthercomprising adsorbent, antioxidant, buffering agent, colorant, flavorant,sweetening agent, antiadherent, binder, diluent, direct compressionexcipient, disintegrant, glidant, lubricant, opaquant, polishing agentor a combination thereof.
 26. The device according to claim 1, whereinthe wall comprises plural preformed passageways.
 27. The deviceaccording to claim 1, wherein the wall comprises plural grades ofcellulose acetate.
 28. A method of treating a disease or disorder thatis therapeutically responsive to lercanidipine comprising administeringto a subject in need thereof an osmotic device according to claim
 1. 29.(canceled)
 30. (canceled)
 31. (canceled)
 32. (canceled)
 33. (canceled)34. (canceled)
 35. (canceled)